Compound having detrusor muscle-contracting activity and urethral sphincter muscle-relaxing activity

ABSTRACT

Since a compound represented by formula (I) wherein all of the symbols are the same as defined in the specification, a salt thereof, a solvate thereof, a prodrug thereof, a mixture with a diastereomer thereof in an arbitrary ratio, or a cyclodextrin clathrate thereof have a contracting activity of bladder detrusor and a relaxing activity of urethral sphincter, they can ameliorate bladder contraction dysfunction and/or urethral relaxation dysfunction, and for example, are effective for underactive bladder. Additionally, the compound of the present invention has little risk of side effects on the urinary system, the circulatory system and the digestive system, and exhibits excellent pharmacokinetics, such as oral absorbability etc. Therefore, the compound of the present invention is useful as a superior agent for preventing, treating and/or ameliorating underactive bladder.

TECHNICAL FIELD

The present invention relates to a compound having a contractingactivity of bladder detrusor and a relaxing activity of urethralsphincter, represented by formula (1):

wherein all of the symbols have the same meanings as defined below, asalt thereof, a solvate thereof, a prodrug thereof, a mixture with adiastereomer thereof in an arbitrary ratio, or a cyclodextrin clathratethereof (hereinafter, the compound represented by formula (I), the saltthereof, the solvate thereof, the prodrug thereof, the mixture with adiastereomer thereof in an arbitrary ratio, or the cyclodextrinclathrate thereof is also referred to simply as “compound of the presentinvention”). The present invention also relates to a pharmaceuticalcomposition comprising the compound of the present invention as anactive ingredient.

BACKGROUND ART

With regard to a symptom wherein bladder cannot be empty (incompletebladder emptying) resulting from insufficient micturition contraction, anew terminology of underactive bladder has recently been proposed.

Underactive bladder is caused by bladder contraction dysfunction, i.e. aclinical condition wherein contractility of the bladder detrusor isdecreased (detrusor underactivity), or a combination of urethralrelaxation dysfunction (lower urinary tract passage dysfunction), i.e. aclinical condition with insufficient relaxation of the urethralsphincter and bladder contraction dysfunction, which is classified intoneurogenic underactive bladder, myogenic underactive bladder,drug-induced underactive bladder, age-related underactive bladder, andunderactive bladder induced by other factors (e.g., underactive bladderdue to lower urinary tract obstruction, infection and stress etc.)depending on the causes.

Examples of causative diseases of neurogenic underactive bladderinclude: peripheral nerve disorders such as diabetes, disc hernia,spinal canal stenosis, Guillain-Barre syndrome, and herpeszoster-induced peripheral neuritis; spinal cord diseases, for example,supranuclear spinal cord injury, spinal cord tumor, cervicalspondylosis, vascular diseases of the spinal cord, spina bifida,myelomeningocele and tethered cord syndrome; and brain diseases, such asdementia, cerebrovascular diseases, Parkinson's disease, spinocerebellardegeneration, olivopontocerebellar atrophy (OPCA), Shy-Drager syndrome,brain tumor, multiple sclerosis, cerebral trauma and encephalitis etc.In some cases, underactive bladder is caused by surgical injury ofpelvic nerve, hypogastric nerve or pudendal nerve controlling voidingfunctions after surgical operations of pelvic viscera (uterine cancer orrectal cancer).

The myogenic underactive bladder is largely caused by a cryptogenicdecreased activity of the bladder detrusor.

Examples of drug-induced underactive bladder include underactive bladderdeveloped by anticholinergic drugs, drugs which inhibit release ofacetylcholine and other factors.

Additionally, aged people generally exhibit dysuria caused by weakenedbladder activity, and as a result, age-related underactive bladderbecomes an important problem in an aging society.

Other examples of factors which cause underactive bladder include lowerurinary tract obstruction caused by prostatic hyperplasia, bladder neckcontracture or uterine prolapse, infections such as cystitis andurethritis, and stress (see Non-Patent Documents 1, 2 and 3).

For the treatment of underactive bladder, drugs which enhance thecontractility of the bladder detrusor or reduce urethral resistancethrough the relaxation of the urethral sphincter are used. For example,cholinergic agents, such as bethanechol and acetylcholinesteraseinhibitors, such as distigmine, are used as drugs for enhancing thecontractility of the bladder detrusor. However, bethanechol alsocontributes to the contraction of the bladder detrusor at the urinecollection period, which causes damage to the urine collection functionof the bladder, and at the same time, has side effects such aslacrimation, perspiration, gastrointestinal disorders, abdominal painetc. Therefore, it is contraindicated for pregnant women, and patientssuffering with peptic ulcer, organic intestinal tract obstruction,asthma, hyperthyroidism etc. As acetylcholinesterase inhibitors, forexample, distigmine and neostigmine, have been used. Sinceacetylcholinesterase inhibitors enhance the activity of acetylcholinereleased from the pelvic nerve endings in urination to enhance thecontraction of the bladder detrusor in urination, they are consideredexcellent drugs when the physiological mechanism of micturition is takeninto consideration. However, since distigmine contracts the bladderdetrusor and also causes the contraction of the urethral sphincter dueto a potent nicotine-like activity thereof to increase urethralresistance, voiding efficiency is not good and effects in terms ofclinical application is insufficient. Additionally, the risk ofhigh-pressure voiding has also been pointed out (see Non-Patent Document4).

As drugs for relaxing the urethral sphincter and reducing urethralresistance, for example, α1 receptor antagonists, such as tamsulosin,prazosin, alfuzosin, naftopidil, urapidil etc. have been used and arereported that they are effective for the amelioration of subjectivesymptoms, such as feeling of residual urine and nocturia. However, sincethere are antihypertensive effects including orthostatic hypotensionetc. as a side effect care should be taken for administration thereof.Additionally, there has been no report demonstrating satisfactoryeffects on underactive bladder.

Namely, drugs currently used for the treatment of underactive bladderare not clinically satisfactory in terms of therapeutic effects andsafety.

On the other hand, Patent Document 1 discloses a compound for improvingthe blood flow in cauda equina nerve tissues, represented by formula(A):

wherein the ring A^(A) represents a 5- or 6-membered cyclic group whichmay contain 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfuratoms or may further have substituents, X^(A) and Y^(A) eachindependently represent a nitrogen atom or a carbon atom, D^(A)represents a hydrocarbon group which may have substituents, E^(A)represents a bond, an oxygen atom, or a sulfur atom which may beoxidized, G^(A) represents a bond, a hydrocarbon group which may havesubstituents or a heterocyclic group which may have substituents, J^(A)represents an acidic group which may be protected, and W^(A) representsa hydrocarbon group which may have substituents. Additionally, it isdisclosed that the compound represented by formula (A) is effective forbladder disorder caused by cauda equina compression (see Patent Document1).

Additionally, a compound having a nerve regeneration or protectionactivity, represented by formula (B):

wherein E^(1B) represents an oxygen atom or a sulfur atom which may beoxidized, R^(B) represents a hydrogen atom or a C₁-C₈ aliphatichydrocarbon group, R^(1B) represents a hydrogen atom or a C₁-C₄aliphatic hydrocarbon group, and R^(2B) represents a hydrocarbon groupwhich may have substituents is disclosed (see Patent Document 2).

The compound of the present invention has not been disclosed in anyliterature.

Additionally, it is neither described nor suggested anywhere: thecompound of the present invention acts on the bladder detrusor andurethral sphincter to enhance the contractility of the bladder detrusorand relax the urethral sphincter on the other hand; can amelioratebladder contraction dysfunction or urethral relaxation dysfunction bythe both activities; and exhibits effectiveness against underactivebladder, including myogenic, drug-induced, age-related etc.Additionally, it is neither described nor suggested that the compound ofthe present invention has little risk of side effects on the urinarysystem, the circulatory system and the digestive system; and hasexcellent pharmacokinetics, including oral absorbability, metabolicstability and efficacy duration.

PRIOR ART DOCUMENTS Patent Documents

-   Patent Document 1: Pamphlet of International Publication No. WO    2005/053707-   Patent Document 2: Pamphlet of International Publication No. WO    2006/129788

Non-Patent Documents

-   Non-Patent Document 1: Nursing Standard, 2005 May 11-17; 19 (35):    57-64; quiz 66-7.-   Non-Patent Document 2: Practice of Intractable and Chronic Dysuria,    Urology View, vol. 2 (5), pp 57-65, 2004-   Non-Patent Document 3: The standardization of terminology in    functions of lower urinary tract: report from the International    Continence Society (ICS) Standardization Steering Committee, Journal    of The Japan Neurogenic Bladder Society, vol. 14 (2), pp 104-118,    issued on Dec. 20, 2003-   Non-Patent Document 4: Diagnosis and Therapy of Neurogenic Bladder,    2nd Ed., pp. 105-106, pp. 139, Igaku-Shoin Ltd. (1990).

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

Since cholinergic agents, acetylcholinesterase inhibitors and α1receptor antagonists, which have been used for the treatment ofunderactive bladder, have only either of an activity for enhancing thecontractility of the bladder detrusor or an activity for relaxing theurethral sphincter as the mechanisms of action thereof, they exhibitinsufficient effects in terms of clinical application. Furthermore,since the drugs act on the autonomic nervous system, there has beenpointed out the expression of side effects in organs other than thebladder.

Under such circumstances, there is a need for a drug that acts on smoothmuscles involved in urination, particularly the bladder detrusor and theurethral sphincter, to contract the bladder and relax the urethra whichachieves very high urination effects.

Since chronic diseases, such as underactive bladder, require long-termadministration of drugs, there is a need for therapeutic agents whichhave little risk of side effects and can be administered orally when thesafety and convenience of patients are taken into consideration.

Means for Solving the Problems

As a result of extensive research, the inventors of the presentinvention found that the compound of the present invention acts on twosmooth muscles, i.e. the bladder detrusor and urethral smooth muscle, toexhibit surprising two activities of enhancing the contraction of thebladder detrusor and relaxing the urethral sphincter on the other hand,and can be provided as a very potent therapeutic agent for underactivebladder to ameliorate both bladder contraction dysfunction and urethralrelaxation dysfunction. The inventors of the present invention alsofound that the compound of the present invention exhibits little risk ofside effects on the urinary system, the circulatory system and thedigestive system, and has excellent pharmacokinetics including oralabsorbability, metabolic stability, efficacy duration etc. to accomplishthe present invention.

Namely, the present invention relates to:

1. A compound represented by formula (I):

wherein

represents an α-configuration;

represents a β-configuration; and

represents an α-configuration, a β-configuration or an arbitrary mixturethereof, a salt thereof, a solvate thereof, a prodrug thereof, or amixture with a diastereomer thereof in an arbitrary ratio, or acyclodextrin clathrate thereof;

2. The compound of the above 1, wherein the compound is

-   (1)    2-[(2-{(1R,5R)-2-oxo-5-[(1E)-7,8,8-trifluoro-4-hydroxy-4-methyl-1,7-octadien-1-yl]cyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylic    acid,-   (2)    2-[(2-{(1R,5R)-2-oxo-5-[(1E,4S)-7,8,8-trifluoro-4-hydroxy-4-methyl-1,7-octadien-1-yl]cyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylic    acid, or-   (3)    2-[(2-{(1R,5R)-2-oxo-5-[(1E,4R)-7,8,8-trifluoro-4-hydroxy-4-methyl-1,7-octadien-1-yl]cyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylic    acid;    3. The mixture in an arbitrary ratio of the above 1, wherein the    compound is    2-[(2-{(1R,5R)-2-oxo-5-[(1E,4S)-7,8,8-trifluoro-4-hydroxy-4-methyl-1,7-octadien-1-yl]cyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylic    acid and the diastereomer is    2-[(2-{(1S,5R)-2-oxo-5-[(1E,4S)-7,8,8-trifluoro-4-hydroxy-4-methyl-1,7-octadien-1-yl]cyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylic    acid;    4. A pharmaceutical composition comprising, as an active ingredient,    a compound represented by formula (I):

wherein all of the symbols have the same meanings as defined in theabove 1, a salt thereof, a solvate thereof, a prodrug thereof, or amixture with a diastereomer thereof in an arbitrary ratio, or acyclodextrin clathrate thereof;

5. The pharmaceutical composition of the above 4, wherein thepharmaceutical composition is an agent for contracting the bladderdetrusor and relaxing the urethral sphincter;6. The pharmaceutical composition of the above 5, wherein thepharmaceutical composition is an agent for preventing, treating and/orameliorating bladder contraction dysfunction and/or urethral relaxationdysfunction;7. The pharmaceutical composition of the above 6, wherein the bladdercontraction dysfunction and/or the urethral relaxation dysfunction isunderactive bladder;8. A medicament comprising a compound represented by formula (I):

wherein all of the symbols have the same meanings as defined in claim 1,a salt thereof, a solvate thereof, a prodrug thereof, a mixture with adiastereomer thereof in an arbitrary ratio, or a cyclodextrin clathratethereof, and at least one drug selected from α1 receptor antagonists andacetylcholinesterase inhibitors in combination;

9. A method for contracting the bladder detrusor and relaxing theurethral sphincter, comprising administering, to a mammal, an effectiveamount of a compound represented by formula (I):

wherein all of the symbols have the same meaning as defined in 1, a saltthereof, a solvate thereof, a prodrug thereof, a mixture with adiastereomer thereof in an arbitrary ratio, or a cyclodextrin clathratethereof;

10. A method for preventing, treating and/or ameliorating bladdercontraction dysfunction and/or urethral relaxation dysfunction,comprising administering, to a mammal, an effective amount of a compoundrepresented by formula (I):

wherein all of the symbols have the same meaning as defined in 1, a saltthereof, a solvate thereof, a prodrug thereof, a mixture with adiastereomer thereof in an arbitrary ratio, or a cyclodextrin clathratethereof;

11. Use of a compound represented by formula (I):

wherein all of the symbols have the same meaning as defined in 1, a saltthereof, a solvate thereof, a prodrug thereof, a mixture with adiastereomer thereof in an arbitrary ratio, or a cyclodextrin clathratethereof, for the preparation of a bladder detrusor-contracting agent anda urethral sphincter-relaxing agent;

12. Use of a compound represented by formula (I):

wherein all of the symbols have the same meaning as defined in 1, a saltthereof, a solvate thereof, a prodrug thereof, a mixture with adiastereomer thereof in an arbitrary ratio, or a cyclodextrin clathratethereof, for the preparation of an agent for preventing, treating and/orameliorating bladder contraction dysfunction and/or urethral relaxationdysfunction;

13. A compound represented by formula (I):

wherein all of the symbols have the same meaning as defined in 1, a saltthereof, a solvate thereof, a prodrug thereof, a mixture with adiastereomer thereof in an arbitrary ratio, or a cyclodextrin clathratethereof, for contracting the bladder detrusor and relaxing the urethralsphincter; and

14. A compound represented by formula (I):

wherein all of the symbols have the same meaning as defined in 1, a saltthereof, a solvate thereof, a prodrug thereof, a mixture with adiastereomer thereof in an arbitrary ratio, or a cyclodextrin clathratethereof, for preventing, treating and/or ameliorating bladdercontraction dysfunction and/or urethral relaxation dysfunction.

Effects of the Invention

The compound of the present invention has a contracting activity ofbladder detrusor and a relaxing activity of urethral sphincter.Therefore, the compound of the present invention can be used toameliorate bladder contraction dysfunction and/or urethral relaxationdysfunction. Thus, the compound of the present invention is effective asan agent for preventing and/or treating underactive bladder.Additionally, the compound of the present invention is effective as anagent for ameliorating various symptoms associated with underactivebladder.

The compound of the present invention has little risk of side effects onthe urinary system. For example, the compound of the present inventionexhibits no storage symptom, such as bladder capacity reduction offeringa high risk to patients suffering with urological diseases, in aneffective dose.

Since the compound of the present invention causes little changes inblood pressure or heart rate on high-dose administration as well as atan effective dose, the compound of the present invention has little riskof side effects in patients suffering from circulatory diseases, such ashypertension. Therefore, the compound of the present invention haslittle effect on the cardiac function.

The compound of the present invention does not exhibit side effects onthe digestive system, for example, digestive symptoms, such as diarrhea,in administration at an effective dose.

The compound of the present invention has a good membrane permeabilityand superior oral absorbability.

The compound of the present invention is stable against hepaticmetabolism and has a low systemic clearance. Therefore, the compound ofthe present invention can exert sustained drug efficacy.

As described above, the compound of the present invention has verypotent urination effects, high safety, and superior pharmacokinetics.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the effect of the compound of the present invention onresidual urinary volume (upper graph) and bladder capacity (lower graph)in underactive bladder models.

FIG. 2 shows the effects of a comparative compound on residual urinaryvolume (upper graph) and bladder capacity (lower graph) in underactivebladder models.

FIG. 3 shows the effects of the compound of the present invention and acomparative compound in blood pressure in normal rats.

FIG. 4 shows the effects of the compound of the present invention and acomparative compound in heart rate in normal rats.

FIG. 5 shows the effects of the compound of the present invention onblood pressure in hypertensive rats.

FIG. 6 shows the effects of a comparative compound on blood pressure inhypertensive rats.

FIG. 7 shows the cardiac performance of the compound of the presentinvention (upper graph) and a comparative compound (lower graph) incynomolgus monkeys.

FIG. 8 shows the double products of the compound of the presentinvention (upper graph) and a comparative compound (lower graph) incynomolgus monkeys.

MODE FOR CARRYING OUT THE INVENTION

The present invention relates to a compound represented by formula (I):

wherein all of the symbols have the same meanings as defined above; asalt thereof, a solvate thereof, a prodrug thereof, a mixture with adiastereomer thereof in an arbitrary ratio, or a cyclodextrin clathratethereof, and a pharmaceutical composition comprising the compound of thepresent invention as an active ingredient.

Unless otherwise specifically indicated herein, it is apparent to thoseskilled in the art that the symbol

represents a binding to the far side of the paper (i.e.α-configuration); the symbol

represents a binding to the front of the paper (i.e. β-configuration);and the symbol

represents α-configuration, β-configuration or a mixture thereof.

As the compound of the present invention,

-   (1)    2-[(2-{(1R,5R)-2-oxo-5-[(1E)-7,8,8-trifluoro-4-hydroxy-4-methyl-1,7-octadien-1-yl]cyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylic    acid,-   (2)    2-[(2-{(1R,5R)-2-oxo-5-[(1E,4S)-7,8,8-trifluoro-4-hydroxy-4-methyl-1,7-octadien-1-yl]cyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylic    acid, or-   (3)    2-[(2-{(1R,5R)-2-oxo-5-[(1E,4R)-7,8,8-trifluoro-4-hydroxy-4-methyl-1,7-octadien-1-yl]cyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylic    acid is preferable. Specifically,    2-[(2-{(1R,5R)-2-oxo-5-[(1E,4S)-7,8,8-trifluoro-4-hydroxy-4-methyl-1,7-octadien-1-yl]cyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylic    acid (Compound 17) described in Example 17 is preferable.

As a salt, a water-soluble one is preferable. Examples of suitable saltsinclude salts of alkali metals (for example, potassium, sodium etc.),salts of alkaline-earth metals (for example, potassium, magnesium etc.),ammonium salts, salts of pharmaceutically acceptable organic amines (forexample, tetramethylammonium, triethylamine, methylamine, dimethylamine,cyclopentylamine, benzylamine, phenethylamine, monoethanolamine,diethanolamine, tris(hydroxymethyl)aminomethane, lysine, arginine andN-methyl-D-glucamine etc.) and acid-addition salts.

The acid-addition salts are preferably water soluble ones. Examples ofsuitable acid-addition salts include inorganic acid salts, such ashydrochlorides, hydrobromides, hydroiodides, sulfates, phosphates andnitrates; and organic acid salts, such as acetates, lactates,tartarates, benzoates, citrates, methanesulfonates, ethanesulfonates,benzenesulfonates, toluenesulfonates, isethionates, glucuronates andgluconates.

The compound represented by formula (I) and salts thereof may also beconverted to corresponding solvates by any suitable methods.

It is preferable that the solvate is a low-toxicity and water-solubleone. Examples of suitable solvates include solvates of water andalcohols (for example, ethanol etc.).

The prodrug of the compound represented by formula (I), the salt thereofor the solvate thereof refers to a compound that is converted in vivo tothe compound represented by formula (I), the salt thereof or the solvatethereof, for example, by enzymatic reactions and reactions with gastricacid. The prodrug of the compound represented by formula (I), the saltthereof or the solvate thereof may be, for example, a compound in whichthe hydroxyl group of the compound represented by formula (I) isacylated, alkylated, phosphorylated or borated (for example, a compoundin which the hydroxyl group of the compound represented by formula (I)is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated,fumarylated or alanylated, dimethylaminomethylcarbonylated); or acompound in which the carboxyl group of the compound represented byformula (I) is esterified or amidated (for example, a compound in whichthe carboxyl group of the compound represented by formula (I) is methylesterified, ethyl esterified, propyl esterified, isopropyl esterified,butyl esterified, isobutyl esterified, tert-butyl esterified, phenylesterified, carboxymethyl esterified, dimethylaminomethyl esterified,pivaloyloxymethyl esterified, 1-{(ethoxycarbonyl)oxy}ethyl esterified,phthalidyl esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methylesterified, 1-{[(cyclohexyloxy)carbonyl]oxy}ethyl esterified or methylamidated). These compounds can be prepared by methods known in the art.The prodrug of the compound represented by formula (I) may be either asolvated or non-solvated form. The prodrug of the compound representedby formula (I) may be one that is converted to the compound representedby formula (I) under physiological conditions, as described in“Development of Medicines”, Vol. 7, “Molecular Design”, pp. 163-198,published by HirokawaShoten in 1990.

The compound represented by formula (I) may be labeled with an isotope(for example, ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³⁵S, ¹⁸F,³⁶Cl, ¹²³I or ¹²⁵I etc.).

The prodrug of the compound represented by formula (I), the salt thereofor the solvate thereof may be, for example, a compound represented byformula (I-a):

wherein R¹ represents a C₁-C₄ alkyl group, such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl or tert-butyl etc., and the symbolshave the same meanings as defined above.

The compound represented by formula (I), the salt thereof, the solvatethereof, the prodrug thereof or the mixture with a diastereomer thereofin an arbitrary ratio can be converted to a cyclodextrin clathrate usingα-, β- or γ-cyclodextrin or a mixture thereof by any the methodsdescribed in the specifications of Japanese Patent Publication Nos.JP-B-S50-3362, JP-B-S52-31404 and JP-B-S61-52146. By converting into thecyclodextrin clathrate, since stability is increased and solubility inwater is increased, the compound is convenient in case of use as a drug.The inclusion of the compound represented by formula (I), the saltthereof, the solvate thereof or the prodrug thereof in cyclodextrin canbe determined by differential scanning calorimetry or powder X-raydiffraction analysis.

The present invention includes a diastereomer mixture of a diastereomerof the compound represented by formula (I) and the compound representedby formula (I) in an arbitrary ratio.

For example, there is2-[(2-{(1S,5R)-2-oxo-5-[(1E,4S)-7,8,8-trifluoro-4-hydroxy-4-methyl-1,7-octadien-1-yl]cyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (Compound 20):

as a diastereomer.

In this connection, as the mixture in an arbitrary ratio, the mixturewherein a ratio of the diastereomer thereof to the compound representedby the formula (I) is 1 to 20% based on the compound represented byformula (I) is preferable. The mixture wherein the ratio of the compoundrepresented by formula (I): the diastereomer=9:1 is more preferable.

[Preparation Methods of the Compound of the Present Invention]

The compounds of the present invention can be prepared by appropriatelymodifying and combining methods known in the art, for example, methodsdescribed in the pamphlets of International Publication No. WO2005/053707, International Publication No. WO 2006/129788 and Synlett2002, No. 1, 239-242 and Comprehensive Organic Transformations: A Guideto Functional Group Preparations, 2nd Edition (Richard C. Larock, JohnWiley & Sons Inc, 1999), methods shown below or methods shown inExamples.

For example, the compound represented by formula (I) can be prepared bysubjecting a compound of Formula (II):

wherein Ac represents an acetyl group, R represents a protecting groupfor the carboxyl group (for example, a C₁-C₄ alkyl group, for example,methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl etc.),and a compound of formula (III):

wherein R¹⁰¹ represents an aryl group (for example,1-phenyl-1H-tetrazolyl, phenyl etc.), R¹⁰² is a protecting group (forexample, trimethylsilyl, tert-butyldimethylsilyl etc.), to the followingreactions, and further deprotecting and oxidizing the acetyl group,followed by deprotecting the protecting group.

The reactions between the compound represented by formula (II) and thecompound represented by formula (III) are known. For example, thereaction is carried out in the presence of a base (for example,potassium hexamethyldisilazide, lithium diisopropylamide or butyllithium etc.) in an organic solvent (for example, anhydroustetrahydrofuran, dimethoxyethane, toluene or dimethylformamide etc.) ata temperature of about −100 to −20° C.

The deprotection reactions of the protecting groups, such as the acetylgroup, are known in the art and can be carried out by the followingprocedure.

Examples of the protecting group for the carboxyl group include a C₁-C₄alkyl group, such as methyl, ethyl, propyl, isopropyl, butyl, isobutylor tert-butyl, an allyl group, a trichloroethyl group, a benzyl (Bn)group, a phenacyl group etc.

Examples of the protecting group for the hydroxyl group include methyl,trityl, methoxymethyl (MOM), 1-ethoxyethyl (EE), methoxyethoxymethyl(MEM), 2-tetrahydropyranyl (THP), trimethylsilyl (TMS), triethylsilyl(TES), tert-butyldimethylsilyl (TBDMS or TBS), tert-butyldiphenylsilyl(TBDPS), acetyl (Ac), pivaloyl, benzoyl, benzyl (Bn), p-methoxybenzyl,allyloxycarbonyl (Alloc) or 2,2,2-trichloroethoxycarbonyl (Troc) etc.

In addition to these protecting groups, any group that can be easily andselectively deprotected may be used as the protecting group for thecarboxyl or hydroxyl group. For example, the protecting groups describedin T. W. Greene, Protective Groups in Organic Synthesis, Wiley, NewYork, 1999 may be used.

The deprotection reactions of protecting groups for a carboxyl orhydroxyl group are well known in the art, for example:

(1) Deprotection by alkali hydrolysis,

(2) Deprotection under acid conditions,

(3) Deprotection by hydrogenolysis,

(4) Deprotection using silyl groups,

(5) Deprotection using metals, and

(6) Deprotection using metal complexes.

These methods will now be explained in detail.

(1) Deprotection by alkali hydrolysis is carried out, for example, usingan alkali metal hydroxide (for example, sodium hydroxide, potassiumhydroxide, lithium hydroxide etc.), an alkaline earth metal hydroxide(for example, barium hydroxide, calcium hydroxide etc.), a carbonate(for example, sodium carbonate, potassium carbonate etc.), an aqueoussolution thereof, or a mixture thereof in an organic solvent (forexample, methanol, tetrahydrofuran, dioxane etc.) at a temperature about0 to about 40° C.

(2) Deprotection under acid conditions is carried out, for example,using an organic acid (for example, acetic acid, trifluoroacetic acid,methanesulfonic acid, p-tosylic acid etc.), an inorganic acid (forexample, hydrochloric acid, sulfuric acid etc.) or a mixture thereof(for example, hydrogen bromide/acetic acid etc.) in an organic solvent(for example, dichloromethane, chloroform, dioxane, ethyl acetate,anisole etc.) at a temperature of about 0 to about 100° C.

(3) Deprotection by hydrogenolysis is carried out, for example, in asolvent (for example, an ether-based solvent (for example,tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether etc.), analcohol-based solvent (for example, methanol, ethanol etc.), abenzene-based solvent (for example, benzene, toluene etc.), aketone-based solvent (for example, acetone, methyl ethyl ketone etc.), anitrile-based solvent (for example, acetonitrile etc.), an amide-basedsolvent (for example, dimethylformamide etc.), water, ethyl acetate,acetic acid or a mixture solvent of two or more thereof) in the presenceof a catalyst (for example, palladium-carbon, palladium black, palladiumhydroxide, platinum oxide, Raney nickel etc.), in a hydrogen atmosphereor in the presence of ammonium formate under ambient pressure or undercompression pressure at a temperature of about 0 to about 200° C.

(4) Deprotection using silyl groups may be carried out, for example,using tetrabutylammonium fluoride in an organic solvent (for example,tetrahydrofuran or acetonitrile etc.) which is miscible with water at atemperature of about 0 to about 40° C.

(5) Deprotection using metals may be carried out, for example, in anacidic solvent (for example, acetic acid, a buffer at a pH of about 4.2to about 7.2, or a mixed solution thereof with an organic solvent suchas tetrahydrofuran etc.) in the presence of zinc powder at a temperatureof about 0 to about 40° C., if necessary, with sonication.

(6) Deprotection using metal complexes is carried out, for example,using a metal complex (for example,tetrakis(triphenylphosphine)palladium (0), bis(triphenylphosphine)palladium (II) dichloride, palladium (II) acetate ortris(triphenylphosphine)rhodium (I) chloride etc.) in an organic solvent(for example, dichloromethane, dimethylformamide, tetrahydrofuran, ethylacetate, acetonitrile, dioxane or ethanol etc.), water or a mixedsolvent thereof in the presence of a trapping reagent (for example,tributyltin hydride, triethylsilane, dimedone, morpholine, diethylamineor pyrrolidine etc.), an organic acid (for example, acetic acid, formicacid or 2-ethylhexanoic acid etc.) and/or an organic acid (for example,sodium 2-ethylhexanoate or potassium 2-ethylhexanoate etc.), with orwithout a phosphine reagent (for example, triphenylphosphine etc.), at atemperature of about 0 to about 40° C.

In addition to these, the deprotection reactions can also be carriedout, for example, by the methods described in T. W. Greene, ProtectiveGroups in Organic Synthesis, Wiley, New York, 1999.

Although it can be easily known by those skilled in the art, byselecting the deprotection reactions, the desired active ingredient ofthe present invention can be easily prepared.

The oxidation is known in the art and may be carried out, for example,using TEMPO reagent (2,2,6,6-tetramethylpiperidine 1-oxyl) and areoxidant (aqueous hydrogen peroxide, sodium hypochlorite,3-chloroperbenzoic acid, iodobenzene diacetate, potassiumperoxymonosulfate (Oxone®) etc.) in an organic solvent (chloroform,dichloromethane, tetrahydrofuran, toluene, acetonitrile, ethyl acetate,water etc.) or a mixed solvent thereof in the presence or absence of aquaternary ammonium salt (tetrabutylammonium chloride,tetrabutylammonium bromide etc.), in the presence or absence of aninorganic salt (sodium bromide, potassium bromide etc.) or in thepresence or absence of an inorganic base (sodium hydrogen carbonate,sodium acetate etc.) at a temperature of about −20 to about 60° C.

The compounds as starting raw materials in the reactions described inthe present specification are known in the art or can be easily preparedby methods known in the art. For example, the compound represented byformula (II) can be prepared, for example, by the method described inthe pamphlet of International Publication No. WO 2006/129788. Thecompound represented by formula (III) can be prepared, for example, bymethods described in Examples described below.

The reactions described in the present specification can be carried outwith using a water bath, oil bath, sand bath or microwave in case ofreactions with heating, which is apparent to those skilled in the art.

In the reactions described in the present specification, a solid reagentcontained in a polymer (for example, polystyrene, polyacrylamide,polypropylene and polyethylene glycol etc.) can be used appropriately.

In the reactions described in the present specification, the reactionproducts can be purified by general techniques, for example,distillation under ambient or reduced pressure, high-performance liquidchromatography using silica gel or magnesium silicate, thin layerchromatography, ion exchange resin chromatography scavenger resinchromatography, column chromatography, washing, recrystallization etc.The purification may be performed after each reaction or after severalreactions.

[Toxicity]

The compound of the present invention causes less side effects and isthus safe enough to use as a drug.

[Applications to Medicaments]

The compound of the present invention acts on two smooth muscles, i.e.the bladder detrusor and the urethral sphincter, associated withunderactive bladder. The compound of the present invention has theability to enhance the contractility of the bladder detrusor and torelax the urethral sphincter on the other hand. Generally, drugs actingon smooth muscles induce the contraction for smooth muscles in anywhereif the drugs promote contraction or induce the relaxation for smoothmuscles in anywhere if the drugs promote relaxation. There is not suchcompound as the compound of the present invention which promotes thecontraction of some smooth muscles while it promotes the relaxation ofother smooth muscles at the same time.

Since the compound of the present invention acts on smooth muscles,particularly the bladder detrusor and the urethral sphincter, to promotethe contraction of the bladder detrusor and the relaxation of theurethral sphincter, it can ameliorate bladder contraction dysfunctionand urethral relaxation dysfunction and is thus effective as an agentfor preventing and/or treating underactive bladder. Additionally, thecompound of the present invention is effective as an agent forameliorating various symptoms associated with underactive bladder, forexample, slow urine stream, split urine stream, blocked urine stream,delayed urination, abdominal pressure voiding, feeling of residualurine, overflow incontinence, anuresis and/or drop of urine afterurination. The compound of the present invention is particularlyeffective as an agent for ameliorating split urine stream, blocked urinestream, abdominal pressure voiding, feeling of residual urine, overflowincontinence, anuresis and/or drop of urine after urination.

The compound of the present invention is also effective in preventingand/or treating spinal canal stenosis, cervical spondylosis, diseases ofthe peripheral nervous system, immune diseases (amyotrophic lateralsclerosis (ALS), multiple sclerosis, Sjogren's syndrome, chronicarticular rheumatism, autoimmune diseases such as systemicerythematodes, rejection responses after organ transplantation, etc.),allergic diseases (for example, bronchial asthma, allergic nasalinflammation, allergic conjunctiva inflammation, atopic dermatitis, foodallergy etc.), nerve cell death, dysmenorrhea, premature birth,misbirth, calvities, neural retinal diseases such as glaucoma, erectiledysfunction, arthritis, lung injury, fibroid lung, emphysema,bronchitis, chronic obstructive respiratory diseases, liver injury,acute hepatitis, cirrhosis, shock, nephritis (for example, acutenephritis, chronic nephritis etc.), renal dysfunction, pancreatitis,systemic inflammatory response syndrome, sepsis, hemophagocyticsyndrome, macrophage activation syndrome, Still's disease, Kawasakidisease, burn injury, systemic granulomatous diseases, colitis ulcerosa,Crohn's disease, hypercytokinemia on dialysis, multiple organdysfunction, bone diseases (bone fracture, refracture, intractablefracture, bone adhesion dysfunction, false joint, osteohalisteresis,bone Paget's disease, rigid spondylitis, cancer bone metastasis,arthrosis deformans, bone•cartilage breakdown in similar diseasesthereof etc.).

The compound of the present invention and other drugs, it may beadministered in combination with other drugs for the purpose of 1)supplementing and/or enhancing the prophylactic and/or therapeuticeffects of the compound, 2) improving the pharmacokinetics andabsorption of the compound, reducing the dose of the compound, and/or 3)alleviating the side effects of the compound.

With regard to the combination agent of the compound of the presentinvention and other drugs, it may be administered in combination withother drugs in the form of a blend in which the two ingredients aremixed in one preparation or in separate preparations. The administrationof the two ingredients in separate preparations includes simultaneousadministration and administration with a time interval. Inadministration with a time interval, it is possible that the compound ofthe present invention is administered in advance and the other drugs areadministered later or it is possible that the other drugs areadministered in advance and the compound of the present invention isadministered later, wherein the administration modes of the twoingredients may be the same as or different from each other.

Examples of drugs suitable for supplementing and/or enhancing theeffects of the compound of the present invention includeacetylcholinesterase inhibitors (for example, distigmine and neostigmineetc.) and α1 acceptor antagonists (for example, tamsulosin, prazosin,alfuzosin, naftopidil, urapidil etc.).

There is no particular limitation on the weight ratio of the compound ofthe present invention to the other drugs.

The other drugs may be a combination of drugs of the same kind or two ormore different kinds.

The other drug for supplementing and/or enhancing the effects of thecompound of the present invention include not only currently found drugsand drugs which will be found based on the above mechanism.

In case where a combination agent of the compound of the presentinvention with the other drugs is used for the above purposes, it isusually administered systemically or locally, or orally or parenterally.

Although the dose may vary depending on the kind of the drug and maydepend on age, weight, symptoms, intended therapeutic effects,administration methods, treatment time etc., the compound of the presentinvention may be usually administered orally at a dose ranging from 1 ngto 100 mg each time per an adult once or several times per day or, maybe administered parenterally at a dose ranging from 0.1 ng to 10 mg eachtime per an adult once or several times per day or alternatively, may becontinuously administered intravenously over a period of 1 to 24 hr perday.

Since the dose may vary depending on various conditions as describedabove, there is a case wherein the dose is sufficient with smalleramount than the dose described above while there is a case whereinadministration with larger scope than the scope described above isnecessary.

In case where the compound of the present invention or the combinationagent of the compound of the present invention and other drug isadministered, it may be used as internal solid preparations or internalliquid preparations for oral administration and injectables, externalpreparations, suppository and inhalations etc. for parenteraladministration.

Examples of internal solid preparations suitable for oral administrationincludes tablets, pills, capsules, powders and granules. The capsulesinclude hard capsules and soft capsules.

The internal solid preparations may be prepared using only one or moreactive ingredients or by mixing one or more active ingredients with forexample, an excipient (lactose, mannitol, glucose, microcrystallinecellulose, starch etc.), a binder (hydroxypropyl cellulose,polyvinylpyrrolidone, magnesium metasilicate etc.), a disintegrant(calcium carboxymethyl cellulose etc.), a lubricant (magnesium stearateetc.), a stabilizer or a dissolution aid (glutamic acid, asparaginicacid etc.) with formulation by techniques known in the art. Ifnecessary, the solid preparations may be covered with a coating agent(for example, white sugar, gelatin, hydroxypropyl cellulose,hydroxypropyl methyl cellulose phthalate etc.) and may be covered withtwo or more layers. Capsules of absorbable materials, for example,gelatin, are also included.

Examples of internal liquid preparations suitable for oraladministration include pharmaceutically acceptable aqueous solutions,suspending agents, emulsifying agents, syrups elixirs etc. In such aliquid preparation, one or more active substances are dissolved,suspended or emulsified in a diluent which is generally used in the art(for example, distilled water, ethanol, a mixed solution thereof etc.).The liquid preparations may contain a wetting agent, a suspending agent,an emulsifying agent, a sweetening agent, a flavoring agent, an aromaticagent, a preservative, a buffering agent, etc.

External formulations for parenteral administration include, forexample, ointments, gels, creams, poultices, patches, liniments,aerosols, inhalations and sprays. Such a preparation includes one ormore active substances and is prepared by methods known or commonly usedin the art.

The ointments are prepared by methods known or commonly used in the art.For example, an ointment may be prepared by triturating or melting oneor more active substances in a base. The ointment base is selected fromthose known or commonly used in the art. Examples of such ointment basesinclude higher fatty acids and higher fatty acid esters (adipic acid,myristic acid, palmitic acid, stearic acid, oleic acid, adipate,myristate, palmitate, stearate, oleate etc.), waxes (beeswax, hard wax,ceresin etc.), surfactants (polyoxyethylene alkyl ether phosphate etc.),higher alcohols (cetanol, stearyl alcohol, cetostearyl alcohol etc.),silicone oil (dimethylpolysiloxane etc.), hydrocarbons (hydrophobicVaseline, white Vaseline, purified lanolin, liquid paraffin etc.),glycols (ethylene glycol, diethylene glycol, propylene glycol,polyethylene glycol, Macrogols etc.), vegetable oils (castor oil, oliveoil, sesame oil, terrapin oil etc.), animal oils (mink oil, egg oil,squalane, squalene etc.), water, absorption accelerators, and anti-itchagents. These ointment bases may be used alone or as a mixture of two ormore thereof. The ointments may further include a moisturizer, apreservative, a stabilizer, an antioxidant, a flavor, etc.

The gels are prepared by methods known or commonly used in the art. Forexample, a gel may be prepared by melting one or more active substancesin a base. The gel base is selected from those known or commonly used inthe art. Examples of such gel bases include lower alcohols (ethanol,isopropyl alcohol etc.), gelling agents (carboxymethyl cellulose,hydroxyethyl cellulose, hydroxypropyl cellulose, ethyl cellulose etc.),neutralizing agents (triethanolamine, diisopropanolamine etc.),surfactants (polyethylene glycol monostearate etc.), gums, water,absorption accelerators, and anti-itch agents. These gel bases may beused alone or as a mixture of two or more thereof. The gels may furtherinclude a preservative, an antioxidant, a flavor, etc.

The creams are prepared by methods known or commonly used in the art.For example, a cream may be prepared by melting or emulsifying one ormore active substances in a base. The cream base is selected from thoseknown or commonly used in the art. Examples of such cream bases includehigher fatty acid esters, lower alcohols, hydrocarbons, polyhydricalcohols (propylene glycol, 1,3-butylene glycol, etc.), higher alcohols(2-hexyldecanol, cetanol etc.), emulsifiers (polyoxyethylene alkylethers, fatty acid esters etc.), water, absorption accelerators, andanti-itch agents. These cream bases may be used alone or as a mixture oftwo or more thereof. The creams may further include a preservative, anantioxidant, a flavor, etc.

The poultices are prepared by methods known or commonly used in the art.For example, a poultice may be prepared by melting one or more activesubstances in a base, kneading, followed by uniformly coating on asupport. The poultice base is selected from those known or commonly usedin the art. Examples of such poultice bases include thickeners (forexample, polyacrylic acid, polyvinylpyrrolidone, arabic gum, starch,gelatin, methyl cellulose etc.), wetting agents (for example, urea,glycerin, propylene glycol etc.), fillers (kaolin, zinc oxide, talc,potassium, magnesium etc.), water, absorption accelerators, tackifiers,and anti-itch agents. These poultice bases may be used alone or as amixture of two or more thereof. The poultices may further include apreservative, an antioxidant, a flavor, etc.

The patches are prepared by methods known or commonly used in the art.For example, a patch may be prepared by melting one or more activesubstances in a base and uniformly coating the melt on a support. Thepatch base is selected from those known or commonly used in the art.Examples of such patch bases include polymeric bases, oils and fats,higher fatty acids, thickeners, and anti-itch agents. These patch basesmay be used alone or as a mixture of two or more thereof. The patchesmay further include a preservative, an antioxidant, a flavor, etc.

The liniments are prepared by methods known or commonly used in the art.For example, a liniment may be prepared by dissolving, suspending oremulsifying one or more active substances in one or more selected fromwater, alcohols (ethanol, polyethylene glycol etc.), higher fatty acids,glycerin, soaps, emulsifiers and suspending agents. The liniments mayfurther include a preservative, an antioxidant, a flavor, etc.

The aerosols, inhalations and sprays may contain a stabilizer, such assodium bisulfite or a buffering agent, for example, an isotonic agentsuch as sodium chloride, sodium citrate or citric acid, in addition to adiluent which is commonly used in the art.

The injectable preparations for parenteral administration may be, forexample, solutions, suspensions, emulsions, and solid injectablepreparations, which are dissolved or suspended in solvents in use. Suchinjectable preparation is used by dissolving, suspending or emulsifyingone or more active substances in a solvent. Examples of suitablesolvents include injectable distilled water, physiological saline,vegetable oils, propylene glycol, polyethylene glycol, alcohols such asethanol, and combinations thereof. The injectable preparations mayinclude stabilizers, dissolution aids (for example, glutamic acid,asparaginic acid, Polysolvate 80® etc.), suspending agents, emulsifyingagents, soothing agents, buffers and preservatives. The injectablepreparations are prepared by sterilization or disinfection in finalsteps. Aseptic solid preparations, for example, lyophilized solidpreparations, can also be used by disinfecting or dissolving in asepticinjectable distilled water or other solvents before use.

Examples of the inhalations for parenteral administration includeaerosols, powders for inhalation or liquids for inhalation. The liquidsfor inhalation may be dissolved or suspended in water or other propermedium before use.

The inhalations are prepared by methods known in the art.

For example, a liquid for inhalation is prepared by selectingappropriately preservatives (benzalkonium chloride, paraben etc.),colorants, buffers (sodium phosphate, sodium acetate etc.), isotonicagents (sodium chloride, concentrated glycerin etc.), thickeners(carboxyvinyl polymer etc.) and absorbefacient, depending on thenecessity.

A powder for inhalation is prepared by selecting appropriatelylubricants (stearic acid, its salts etc.), binders (starch, dextrinetc.), excipients (lactose, cellulose etc.), colorants, preservatives(benzalkonium chloride, paraben etc.) and absorbefacient, depending onthe necessity.

For administration of liquids for inhalation, sprayers (atomizers,nebulizers) are usually used. For administration of powders forinhalation, inhalators for the administration of powdery drugs areusually used.

Other compositions for parenteral administration include, one or moreactive substances and are for example, suppositories for intrarectaladministration and pessaries for intravaginal administration.

EXAMPLES

The present invention will be explained in detail by Examples. However,the present invention is not limited by the Examples.

The solvents in the parenthesis indicated in the separated portion bythe chromatography and TLC represent eluting or developing solvents usedand their ratio is volume ratio.

NMR data are ¹H-NMR data in 300 MHz unless otherwise specified. Theparentheses in the NMR data represent solvents used for measurement.

The compounds used herein were named by a computer program which nameschemical names according to the IUPAC rules, ACD/Name Batch (registeredtrademark), or according to IUPAC nomenclature. For example,

was named as2-[(2-{(1R,5R)-2-oxo-5-[(1E,4S)-7,8,8-trifluoro-4-hydroxy-4-methyl-1,7-octadien-1-yl]cyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid.

Preparation Examples Example 14,5,5-trifluoro-N-methoxy-N-methyl-4-penteneamide (Compound 1)

N,O-dimethylhydroxyamine hydrochloride (3.5 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.9 g) andtriethylamine (9.2 mL) were added to a solution of4,5,5-trifluoropent-4-enoic acid (CAS No. 110003-22-0 (5.0 g)) inmethylene chloride solution (64 mL) in a cold-water bath and stirringwas carried out at room temperature overnight. The reaction solution wasconcentrated and diluted with ethyl acetate. The dilute solution waswashed with 1 N hydrochloric acid, water and saturated brine; dried withanhydrous sodium sulfate; and concentrated to obtain the title compound(6.4 g) having the following physical properties:

TLC: Rf 0.50 (ethyl acetate:hexane=1:2);

NMR (CDCl₃): δ 2.51-2.77 (m, 4H), 3.19 (s, 3H), 3.69 (s, 3H).

Example 2 Ethyl 6,7,7-trifluoro-3-oxo-6-heptenoate (Compound 2)

Ethyl acetate (4.8 mL) was slowly added dropwise to a lithiumhexamethyldisilazide/tetrahydrofuran solution (1 M, 48 mL) at −78° C.,followed by stirring for 30 min. The solution of compound 1 (6.4 g) inanhydrous tetrahydrofuran (33 mL) was slowly added dropwise to thereaction solution at the same temperature followed by stirring for 30min. To the reaction solution, 2 N hydrochloric acid (30 mL) was added,followed by extraction with ethyl acetate. The organic layer was washedwith water and saturated brine; dried with anhydrous sodium sulfate; andconcentrated. The resulting residue was purified by silica gel columnchromatography (hexane:ethyl acetate=20:1→15:1) to obtain the titlecompound (4.94 g) having the following physical properties:

TLC: Rf 0.63 (ethyl acetate:hexane=1:2);

NMR (CDCl₃): δ 1.29 (t, J=7.1 Hz, 3H), 2.50-2.71 (m, 2H), 2.83 (t, J=7.2Hz, 2H), 3.47 (s, 2H), 4.21 (q, 2H).

Example 3 6,7,7-trifluoro-6-heptene-1,3-diol (Compound 3)

A solution of compound 2 (4.71 g) in tert-butyl methyl ether (52 mL) wasslowly added dropwise to boron lithium hydride (1.4 g) under icecooling, followed by stirring at room temperature for 4 hr. The reactionsolution was poured into a saturated aqueous solution of ammoniumchloride under ice cooling and washed with ethyl acetate. The organiclayer was washed with saturated brine; dried with sodium sulfate; andconcentrated to obtain the title compound (3.87 g) having the followingphysical properties:

TLC: Rf 0.31 (ethyl acetate:hexane=2:1);

NMR (CDCl₃): δ 1.66-1.83 (m, 4H), 2.17-2.66 (m, 2H), 3.71-4.06 (m, 3H).

Example 46,7,7-trifluoro-1-[(1-phenyl-1H-tetrazol-5-yl)thio]-6-hepten-3-ol(Compound 4)

Compound 3 (3.87 g) was dissolved in toluene (50 mL) and a 2N aqueoussolution of sodium hydroxide (50 mL), and tetrabutylammonium bromide(700 mg) and tosyl chloride chloride (4.10 g) were added thereto underice cooling, followed by stirring for 30 min. To the reaction solution1-phenyl-1H-tetrazole-5-thiol (4.60 g) was added, followed by stirringat 60° C. overnight. The reaction solution was poured into water andextracted with tert-butyl methyl ether. The organic layer was washedwith saturated brine; dried with sodium sulfate; and concentrated. Theresulting residue was purified by silica gel column chromatography(hexane:ethyl acetate=4:1→7:3) to obtain the title compound (5.43 g)having the following physical properties:

TLC: Rf 0.37 (ethyl acetate:hexane=2:1);

NMR (CDCl₃): δ 1.64-1.83 (m, 2H), 1.88-2.02 (m, 2H), 2.31-2.61 (m, 2H),3.34-3.88 (m, 3H), 7.46-7.69 (m, 5H).

Example 56,7,7-trifluoro-1-[(1-phenyl-1H-tetrazol-5-yl)thio]-6-hepten-3-one(Compound 5)

Potassium bromide (830 mg), 2,2,6,6-tetramethylpiperidine-1-oxyl (199mg) and an aqueous solution of sodium hypochlorite (10%, 6.1 mL) wereadded to a acetonitrile solution (32 mL) of compound 4 (2.18 g) underice cooling, followed by stirring for 2 hr. A saturated aqueous solutionof sodium thiosulfate was added to the reaction solution at the sametemperature, followed by extraction with ethyl acetate. The organiclayer was washed with water and saturated brine; dried with anhydroussodium sulfate; and concentrated to obtain the title compound (2.17 g)having the following physical properties:

TLC: Rf 0.50 (ethyl acetate:hexane=1:2);

NMR (CDCl₃): δ 2.48-2.77 (m, 4H), 3.14 (t, J=6.4 Hz, 2H), 3.57 (t, J=6.4Hz, 2H), 7.54 (s, 5H).

Example 66,7,7-trifluoro-3-methyl-1-[(1-phenyl-1H-tetrazol-5-yl)thio]-6-hepten-3-ol(Compound 6)

A methyl magnesium bromide/diethyl ether solution (3.0 M, 4.2 mL) wasadded to an anhydrous tetrahydrofuran solution (22 mL) of compound 5(2.17 g) at −78° C. The mixed solution was stirred for 30 min at thesame temperature and for 30 min under ice cooling. A saturated aqueoussolution of sodium hydrogen carbonate was added to the reaction solutionunder ice cooling, followed by extraction with ethyl acetate. Theorganic layer was washed with water and saturated brine; dried withanhydrous sodium sulfate; and concentrated. The resulting residue waspurified by silica gel column chromatography (hexane:ethyl acetate=7:3)to obtain the title compound (1.88 g) having the following physicalproperties:

TLC: Rf 0.39 (ethyl acetate:hexane=1:2);

NMR (CDCl₃): δ 1.29 (s, 3H), 1.69-1.92 (m, 2H), 1.99-2.19 (m, 2H),2.30-2.59 (m, 2H), 3.33-3.67 (m, 2H), 7.42-7.70 (m, 5H).

Example 76,7,7-trifluoro-3-methyl-1-[(1-phenyl-1H-tetrazol-5-yl)sulfonyl]-6-hepten-3-ol(Compound 7)

Hexaammonium heptamolybdenum tetrahydrate (318 mg) and aqueous hydrogenperoxide (30%, 1.8 mL) were added to a methanol solution (26 mL) ofcompound 6 (1.84 g) under ice cooling, followed by stirring at roomtemperature overnight. A saturated aqueous solution of sodiumthiosulfate was added to the reaction solution under ice cooling,followed by extraction with ethyl acetate. The organic layer was washedwith water and saturated brine; dried with anhydrous sodium sulfate; andconcentrated to obtain the title compound (2.0 g) having the followingphysical properties:

TLC: Rf 0.41 (ethyl acetate:hexane=1:2);

NMR (CDCl₃): δ 1.30 (s, 3H), 1.69-1.86 (m, 2H), 2.06-2.24 (m, 2H),2.30-2.57 (m, 2H), 3.80-4.00 (m, 2H), 7.51-7.78 (m, 5H).

Example 81-phenyl-5-({6,7,7-trifluoro-3-methyl-3-[(trimethylsilyl)oxy]-6-hepten-1-yl}sulfonyl)-1H-tetrazole(Compound 8)

Imidazole (524 mg) and trimethylsilyl chloride (0.79 mL) were added to asolution of compound 7 (2.0 g) in dimethylformamide (11 mL) under icecooling, followed by stirring at room temperature for 5 hr. The reactionsolution was poured into water and extracted with ethyl acetate. Theorganic layer was washed with saturated brine; dried with anhydroussodium sulfate; and concentrated. The resulting residue was purified bysilica gel column chromatography (hexane:ethyl acetate=9:1) to obtainthe title compound (2.16 g) having the following physical properties:

TLC: Rf 0.72 (ethyl acetate:hexane=1:2);

NMR (CDCl₃): δ 0.15 (s, 9H), 1.35 (s, 3H), 1.66-1.86 (m, 2H), 1.96-2.19(m, 2H), 2.25-2.46 (m, 2H), 3.74-3.88 (m, 2H), 7.56-7.67 (m, 3H),7.68-7.74 (m, 2H).

Example 9 Ethyl2-({2-[(1R,2S,5S)-2-(acetyloxy)-5-formylcyclopentyl]ethyl}thio)-1,3-thiazole-4-carboxylate(Compound 9)

Triethylamine (3.7 mL) and sulfur trioxide.pyridine complex (1.7 g) wereadded to a dimethyl sulfoxide (4.0 mL)/ethyl acetate (8.0 mL) solutionof ethyl2-({2-[(1R,2S,5S)-2-(acetyloxy)-5-(hydroxymethyl)cyclopentyl]ethyl}thio)-1,3-thiazole-4-carboxylate(500 mg) (see compound 7 described in the pamphlet of InternationalPublication No. WO 2006/129788) at 10° C., followed by stirring at roomtemperature for 30 min. To the reaction solution, 1 N hydrochloric acidwas added, followed by extraction with ethyl acetate. The organic layerwas washed with water and saturated brine; dried with anhydrous sodiumsulfate; and concentrated to obtain the title compound (497 mg) havingthe following physical properties:

TLC: Rf 0.27 (hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 1.32-1.49 (m, 3H) 1.78-2.15 (m, 9H) 2.35-2.51 (m, 1H)2.69-2.84 (m, 1H) 3.10-3.31 (m, 2H) 4.32-4.48 (m, 2H) 5.29-5.37 (m, 1H)8.02 (s, 1H) 9.67 (d, J=2.74 Hz, 1H).

Example 10 Ethyl2-{[2-((1R,2S,5R)-2-(acetyloxy)-5-{(1E)-7,8,8-trifluoro-4-methyl-4-[(trimethylsilyl)oxy]-1,7-octadien-1-yl}cyclopentyl)ethyl]thio}-1,3-thiazole-4-carboxylate(Compound 10)

A potassium hexamethyldisilazide/toluene solution (0.5 M, 4.8 mL) wasslowly added dropwise to a 1,2-dimethoxyethane (8.0 mL) solution ofcompound 8 (1.13 g) at −78° C., followed by stirring at the sametemperature for 30 min. To the reaction solution, a 1,2-dimethoxyethanesolution (5.0 mL) of compound 9 (461 mg) in was slowly added dropwise atthe same temperature. After string at the same temperature for 30 min,the temperature was raised to 0° C. A saturated aqueous solution ofsodium hydrogen carbonate was added, followed by extraction with ethylacetate. The organic layer was washed with water and saturated brine;dried with anhydrous sodium sulfate; and concentrated. The resultingresidue was purified by silica gel column chromatography (hexane:ethylacetate=8:1) to obtain the title compound (703 mg) having the followingphysical properties:

TLC: Rf 0.71 (ethyl acetate:hexane=1:2);

NMR (CDCl₃): δ 0.10 (s, 9H), 1.39 (t, J=7.1 Hz, 3H), 1.49-2.48 (m, 17H),3.10-3.40 (m, 2H), 4.40 (q, J=7.1 Hz, 2H), 5.18-5.53 (m, 3H), 8.02 (s,1H).

Example 112-[(2-{(1R,2S,5R)-2-hydroxy-5-[(1E)-7,8,8-trifluoro-4-hydroxy-4-methyl-1,7-octadien-1-yl]cyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (Compound 11)

To an ethanol solution (6.0 mL) of compound 10 (703 mg), 2 N aqueoussolution of sodium hydroxide (2.4 mL) was added under ice cooling,followed by stirring at room temperature overnight. To the reactionsolution, 1 N hydrochloric acid was added at the same temperature,followed by stirring for 30 min. Water was added to the reactionsolution, followed by extraction with ethyl acetate. The organic layerwas washed with saturated brine; dried with anhydrous sodium sulfate;and concentrated to obtain the title compound (538 mg) having thefollowing physical properties:

TLC: Rf 0.21 (ethyl acetate:methanol=5:1);

NMR (CDCl₃): δ 1.19 (s, 3H), 1.32-1.50 (m, 2H), 1.61-1.92 (m, 4H),1.94-2.56 (m, 8H), 2.81-2.99 (m, 1H), 3.49-3.67 (m, 1H), 4.56 (m, 1H),5.27-5.62 (m, 2H), 8.08 (s, 1H).

Example 122-[(2-{(1R,2S,5R)-2-(acetyloxy)-5-[(1E)-7,8,8-trifluoro-4-hydroxy-4-methyl-1,7-octadien-1-yl]cyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (Compound 12)

Anhydrous acetic acid (0.33 mL) was added to a pyridine solution (6.0mL) of compound 11 (538 mg) under ice cooling, followed by stirring atroom temperature overnight. The reaction solution was poured into 1 Nhydrochloric acid and extracted with ethyl acetate. The organic layerwas washed with saturated brine; dried with anhydrous sodium sulfate;and concentrated to obtain the title compound (589 mg) having thefollowing physical properties:

TLC: Rf 0.27 (ethyl acetate:methanol=5:1);

NMR (CDCl₃): δ 1.16-1.21 (m, 3H), 1.34-2.54 (m, 17H), 3.10-3.53 (m, 2H),5.33-5.61 (m, 3H), 8.11 (s, 1H).

Example 13(10S,12E,13aR,16S,16aR)-10-methyl-8-oxo-10-(3,4,4-trifluoro-3-buten-1-yl)-1,10,11,13a,14,15,16,16a-octahydro-2H,8H-7,4-(azeno)cyclopenta[j][1,5,7]oxadithiacyclopentadecyn-16-ylacetate (low-polarity form: compound 13A)(10R,12E,13aR,16S,16aR)-10-methyl-8-oxo-10-(3,4,4-trifluoro-3-buten-1-yl)-1,10,11,13a,14,15,16,16a-octahydro-2H,8H-7,4-(azeno)cyclopenta[j][1,5,7]oxadithiacyclopentadecyn-16-ylacetate (high-polarity form: compound 13B)

To a toluene solution (58 mL) of compound 12 (589 mg),4,4-dimethylaminopyridine (567 mg) was added at room temperature. Thereaction solution was heated to 100° C., and 2,4,6-trichlorobenzoylchloride (0.37 mL) was added thereto. After stirring for 15 min, coolingto room temperature was carried out. The reaction solution was pouredinto a saturated aqueous solution of sodium hydrogen carbonate andextracted with ethyl acetate. The organic layer was washed with waterand saturated brine; dried with anhydrous sodium sulfate; andconcentrated. The resulting residue was purified by silica gel columnchromatography (hexane:ethyl acetate=15:1) to obtain the title compounds(compound 13A: 200 mg, compound 13B: 120 mg) having the followingphysical properties:

Compound 13A:

TLC: Rf 0.49 (ethyl acetate:hexane=1:4);

NMR (CDCl₃): δ 1.32-2.22 (m, 14H), 2.27-2.50 (m, 3H), 2.55-2.75 (m, 2H),2.78-3.00 (m, 2H), 3.22-3.40 (m, 1H), 5.26-5.35 (m, 1H), 5.37-5.50 (m,1H), 5.55-5.71 (m, 1H), 7.98 (s, 1H).

Compound 13B:

TLC: Rf 0.46 (ethyl acetate:hexane=1:4);

NMR (CDCl₃): δ 1.32-2.61 (m, 19H), 2.80-3.01 (m, 2H), 3.18-3.32 (m, 1H),5.26-5.36 (m, 1H), 5.44-5.69 (m, 2H), 7.96 (s, 1H).

Example 142-[(2-{(1R,2S,5R)-2-hydroxy-5-[(1E,4S)-7,8,8-trifluoro-4-hydroxy-4-methyl-1,7-octadien-1-yl]cyclopropyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (Compound 14)

Compound 13A (200 mg) was dissolved in a mixed solvent of methanol (1.0mL) and tetrahydrofuran (2.0 mL), and a 2 N aqueous solution of sodiumhydroxide (0.62 mL) was added, followed by stirring at room temperatureovernight. The reaction solution was poured into 1 N hydrochloric acidand extracted with ethyl acetate. The organic layer was washed withwater and saturated brine; dried with anhydrous sodium sulfate; andconcentrated to obtain the title compound (190 mg) having the followingphysical properties:

TLC: Rf 0.21 (ethyl acetate:methanol=5:1);

NMR (CDCl₃): δ 1.19 (s, 3H), 1.33-1.52 (m, 2H), 1.59-2.14 (m, 7H), 2.20(d, J=6.6 Hz, 2H), 2.25-2.51 (m, 3H), 2.81-3.01 (m, 1H), 3.50-3.67 (m,1H), 4.51-4.59 (m, 1H), 5.31-5.54 (m, 2H), 8.07 (s, 1H).

Example 15 Methyl2-[(2-{(1R,2S,5R)-2-hydroxy-5-[(1E,4S)-7,8,8-trifluoro-4-hydroxy-4-methyl-1,7-octadien-1-yl]cyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylate(Compound 15)

Potassium carbonate (340 mg) and methyl iodide (0.09 mL) were added to adimethylformamide solution (2.1 mL) of compound 14 (190 mg), followed bystirring at room temperature overnight. The reaction solution was pouredinto water and extracted with ethyl acetate. The organic layer waswashed with water and saturated brine; dried with anhydrous sodiumsulfate; and concentrated to obtain the title compound (196 mg) havingthe following physical properties:

TLC: Rf 0.36 (ethyl acetate:hexane=1:1);

NMR (CDCl₃): δ 1.18 (s, 3H), 1.29-1.49 (m, 2H), 1.53-1.88 (m, 4H),1.91-2.11 (m, 3H), 2.19 (d, J=6.2 Hz, 2H), 2.27-2.52 (m, 3H), 2.82-2.97(m, 1H), 3.50-3.68 (m, 1H), 3.92 (s, 3H), 4.42-4.53 (m, 1H), 5.30-5.51(m, 2H), 7.98 (s, 1H).

Example 16 Methyl2-[(2-{(1R,5R)-2-oxo-5-[(1E,4S)-7,8,8-trifluoro-4-hydroxy-4-methyl-1,7-octadien-1-yl]cyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylate(Compound 16)

Diisopropylethylamine (0.43 mL) and sulfur trioxide.pyridine complex(196 mg) were added to a dimethyl sulfoxide (1.4 mL)/ethyl acetate (2.8mL) solution of compound 15 (196 mg) under ice cooling, followed bystirring for 15 min. Water was added to the reaction solution, followedby extraction with ethyl acetate. The organic layer was washed with 1 Nhydrochloric acid, water and saturated brine; dried with anhydroussodium sulfate; and concentrated. The resulting residue was purified bysilica gel column chromatography (hexane:ethyl acetate=3:2) to obtainthe title compound (152 mg) having the following physical properties:

TLC: Rf 0.45 (ethyl acetate:hexane=1:1);

NMR (CDCl₃): δ 1.16 (s, 3H), 1.46-2.63 (m, 14H), 3.37-3.49 (m, 2H), 3.91(s, 3H), 5.45-5.57 (m, 1H), 5.61-5.76 (m, 1H), 8.01 (s, 1H).

Example 172-[(2-{(1R,5R)-2-oxo-5-[(1E,4S)-7,8,8-trifluoro-4-hydroxy-4-methyl-1,7-octadien-1-yl]cyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (Compound 17)

Compound 16 (152 mg) was dissolved in 1,2-dimethoxyethane (2.0 mL)/water(1.0 mL), and lithium hydroxide (16.0 mg) was added thereto under icecooling, followed by stirring at room temperature for 2 hr. The reactionsolution was poured into a 5% aqueous solution of potassium hydrogensulfate and extracted with ethyl acetate. The organic layer was washedwith water and saturated brine; dried with anhydrous sodium sulfate; andconcentrated. The resulting residue was purified by silica gel columnchromatography (hexane:ethyl acetate=1:1→methanol:ethyl acetate=1:10) toobtain the title compound (127 mg, amorphous, viscous oil) having thefollowing physical properties:

TLC: Rf 0.20 (ethyl acetate:methanol=5:1);

NMR (CDCl₃): δ 1.21 (s, 3H), 1.55-1.80 (m, 3H), 1.88-2.60 (m, 11H), 3.37(t, J=7.50 Hz, 2H), 5.54 (dd, J=14.82, 7.68 Hz, 1H), 5.62-5.76 (m, 1H),8.11 (s, 1H).

Example 182-[(2-{(1R,5R)-2-oxo-5-[(1E,4R)-7,8,8-trifluoro-4-hydroxy-4-methyl-1,7-octadien-1-yl]cyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (Compound 18)

The same procedure of Examples 14→15→16→17 was carried out except thatcompound 13B was used instead of compound 13A, to obtain the titlecompound (57.3 mg, amorphous, viscous oil).

TLC: Rf 0.20 (ethyl acetate:methanol=5:1);

NMR (CDCl₃): δ 1.21 (s, 3H), 1.56-1.79 (m, 3H), 1.91-2.59 (m, 11H),3.31-3.42 (m, 2H), 5.54 (dd, J=15.57, 8.04 Hz, 1H), 5.61-5.77 (m, 1H),8.11 (s, 1H).

Example 192-[(2-{(1R,5R)-2-oxo-5-[(1E)-7,8,8-trifluoro-4-hydroxy-4-methyl-1,7-octadien-1-yl]cyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (Compound 19)

The same procedure of Examples 15→16→17 was carried out except thatcompound 11 was used instead of compound 14, to obtain the titlecompound (7.6 mg, amorphous, viscous oil).

TLC: Rf 0.71 (ethyl acetate:methanol:acetic acid=8:1:1);

NMR (CDCl₃): δ 1.21 (s, 3H), 1.56-1.80 (m, 3H), 1.90-2.60 (m, 11H),3.18-3.62 (m, 2H), 5.54 (dd, J=15.3, 7.8 Hz, 1H), 5.60-5.75 (m, 1H),8.10 (s, 1H).

Example 202-[(2-{(1S,5R)-2-oxo-5-[(1E,4S)-7,8,8-trifluoro-4-hydroxy-4-methyl-1,7-octadien-1-yl]cyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (Compound 20)

TLC: Rf 0.50 (methanol:chloroform=1:9);

NMR (CDCl₃): δ 8.13 (s, 1H), 5.66 (dt, 3=15, 6 Hz, 1H), 5.40 (dd, J=15,9 Hz, 1H), 3.50-3.25 (m, 2H), 3.15-3.05 (m, 1H), 3.00-2.50 (m, 1H),2.50-2.25 (m, 4H), 2.23 (d, J=6 Hz, 2H), 2.20-2.00 (m, 3H), 2.00-1.85(m, 1H), 1.85-1.60 (m, 3H), 1.21 (s, 3H).

Example 21 Methyl2-[(2-{(1R,5S)-2-oxo-5-[(1E,4S)-7,8,8-trifluoro-4-hydroxy-4-methyl-1,7-octadien-1-yl]-3-cyclopenten-1-yl}ethyl)thio]-1,3-thiazole-4-carboxylate(Compound 21)

TLC: Rf 0.38 (ethyl acetate:hexane=1:1);

NMR (CDCl₃): δ 1.19 (s, 3H), 1.60-1.80 (m, 2H), 1.95 (m, 1H), 2.23 (d,J=7.5 Hz, 2H), 2.20-2.48 (m, 4H), 3.30 (m, 1H), 3.44-3.58 (m, 2H), 3.91(s, 3H), 5.48 (dd, J=15.0, 8.4 Hz, 1H), 5.84 (dt, J=15.0, 7.2 Hz, 1H),6.17 (dd, J=5.7, 2.1 Hz, 1H), 7.49 (dd, J=5.7, 2.4 Hz, 1H), 8.01 (s,1H).

Example 22 β-cyclodextrin clathrate of sodium2-[(2-{(1R,5R)-2-oxo-5-[(1E,4S)-7,8,8-trifluoro-4-hydroxy-4-methyl-1,7-octadien-1-yl]cyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylate(mixing molar ratio=1:3)

The sodium salt of compound 17 (8.12 mg) and β-cyclodextrin (56.88 mg)were weighed and dissolved in purified water (5 mL). The solution wasallowed to stand for 30 min; freeze-dried; and dried under reducedpressure at room temperature overnight to obtain the title compound(64.8 mg).

NMR (D₂O)

Peaks from sodium2-[(2-{(1R,5R)-2-oxo-5-[(1E,4S)-7,8,8-trifluoro-4-hydroxy-4-methyl-1,7-octadien-1-yl]cyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylate:7.81 (s, 1H), 5.57-5.40 (m, 2H), 3.26-3.19 (m, 2H), 2.49 (m, 1H),2.35-1.98 (m, 9H), 1.83 (m, 1H), 1.64 (m, 1H), 1.55-1.46 (m, 2H), 1.01(s, 3H).

Peaks from β-cyclodextrin: 4.91 (d, J=3.6 Hz, 1H), 3.81-3.63 (m, 4H),3.51-3.41 (m, 2H).

Biological Examples

It was demonstrated by the following experiments that the compound ofthe present invention is a compound which has activity to contractbladder and relax the urethra; causes less side effects; and has goodpharmacokinetics such as oral absorbency.

Additionally, the following comparative experiments were also conductedto demonstrate that the compound of the present invention has betterpharmacokinetics such as safety and oral absorbency than the compoundsdescribed in the prior art documents.

Comparative compound A:2-[(2-{(1R,2R)-2-[(1E,4S)-4-hydroxy-4,7-dimethyl-1,7-octadien-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (the 4S-form of compound 18-6 described in the pamphlet ofInternational Publication No. WO 2006/129788)

Comparative compound B:2-[(2-{(1R,2R)-2-[(1E,4S)-4-hydroxy-4-methyl-1-nonen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (the compound 17-1 described in the pamphlet of InternationalPublication No. WO 2006/129788)

Comparative compound C:2-[(2-{(1R,5R)-2-oxo-5-[(1E,4S)-8,8,8-trifluoro-4-hydroxy-4-methyl-1-octenyl]cyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (the 4S-form of the compound 18-1 described in the pamphlet ofInternational Publication No. WO 2006/129788)

Comparative compound D:2-[(2-{(1R,2R)-2-[(1E,4S)-4-hydroxy-4-methyl-1,7-octadien-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (the 4S-form of the compound 32 described in the pamphlet ofInternational Publication No. WO 2006/129788)

Comparative compound E:2-[(2-{(4S)-2-oxo-4-[(1E,4S)-8,8,8-trifluoro-4-hydroxy-4-methyl-1-octenyl]-1,3-oxazolidin-3-yl}ethyl)sulfanyl]-1,3-thiazole-4-carboxylicacid (the compound 65-2 described in the pamphlet of InternationalPublication No. WO2005/053707)

(1) Evaluation of the Activity to Contract the Bladder Detrusor andRelax the Urethral Sphincter <Construction of Incised Specimens>

Rats were anesthetized with pentobarbital, followed by abdominalincision to remove the bladders and the urethras. The bladder bodieswere cut in the longitudinal direction to prepare strip specimens with asize of about 10×3 mm. Additionally, each of the urethras was also cutin the longitudinal direction to prepare specimens with a size of about10×3 mm. The prepared specimens were suspended in Krebs buffer (37° C.,5 mL), which was aerated with a mixed gas of 95% O₂ and 5% CO₂. Thetension values of the specimens were measured using a Magnus systemequipped with an isometric transducer and an amplifier, and the measuredvalues were recorded on a computer via a data collection system.

<Effects of Compounds on Bladders>

The specimens were suspended with a load of about 0.5 g. More than 1 hrlater, potassium chloride (100 mmol/L) was added and the maximalcontraction response was observed. After washing with Krebs buffer, thespecimens were suspended with a load of about 0.5 g for stabilization. Apotassium chloride solution (7.5 mmol/L) was added to induce thecontraction of the specimens. After the contraction-inducing responsewas stabilized, the test compound was added in a cumulative manner andthe response was observed before and after the treatment with the drug.

<Effect of Compounds on Urethras>

The specimens were suspended with a load of about 0.5 g. More than 1 hrlater, potassium chloride (100 mmol/L) was added to the suspension andthe maximal contraction response was observed. After washing with Krebsbuffer, the specimens were suspended with a load of about 0.5 g forstabilization. Thereafter, a phenylephrine (100 μmol/L) was added to thesuspension to induce the contraction of the specimens. Afterstabilization of the contraction-inducing response, the test compoundwas added in a cumulative manner and the response was observed beforeand after the treatment of the drug.

<Results>

The results are given in Tables 1 and 2.

TABLE 1 Contractility of the bladder detrusor according to the compoundconcentration treated (% of 7.5 mmol/L KCl) 0 1 10 100 1 10 nmol/Lnmol/L nmol/L nmol/L μmol/L μmol/L Vehicle 3 0 −4 −12 −14 −15 (n = 11)Compound 17 3 −2 23 100 180 259 (n = 4)

TABLE 2 Contractility of the urethral sphincter according to thecompound concentration treated (% of phenylephrine) 0 1 10 100 1 10nmol/L nmol/L nmol/L nmol/L μmol/L μmol/L Vehicle −4 −11 −13 −25 −38 −44(n = 11) Compound 17 5 −2 −9 −36 −83 −89 (n = 4)

From the above experimental results, the compound 17 contracted thebladder detrusor and relaxed the urethral sphincter. Therefore, thecompound of the present invention acts on the bladder and urethra toameliorate bladder contraction dysfunction and urethral relaxationdysfunction, which is effective for underactive bladder.

(2) Measurement of Residual Urinary Volumes and Bladder Capacities inUnderactive Bladder Models <Construction of Animal Models and Indwellingof Catheters>

The underactive bladder models were constructed in accordance with thefollowing procedure. Female Wistar rats (8 to 9 weeks age) wereanesthetized by intraperitoneal administration of Somnopentyl (40mg/kg), followed by dorsal shaving, and fixed in abdominal positions.Each of the dorsal areas was disinfected with chlorhexidine gluconate(5% hibitane liquid). The waist area was median-incised to expose thespinal column. After excision of the fifth lumbar spinous process, asilicone rubber was inserted into the sixth lumbar direction from a holebored by a mini drill. For the purpose of avoiding infections, aftercompletion of the surgical operation, benzylpenicillin potassium (25000U/0.25 mL/body) was added dropwise to the incised area. The muscle andskin of the incised area were sutured with silk threads, and iodinetincture was applied to the sutured area. After the operation,maintenance of voiding was carried out by manual compressions threetimes daily. For the purpose of avoiding infections, potassiumpenicillin G (1.25 units/body) was administered subcutaneously. Morethan 5 days prior to cystometric evaluation, a catheter forcystometrogram was indwelled in the bladder. Anesthesia with sodiumpentobarbital (40 mg/kg by intraperitoneal administration) and incisionalong the midline of the abdomen were carried out, followed by incisionof the apex of the bladder. A catheter for cystometrogram filled withphysiological saline was inserted into the bladder from a hole of theapical area, and fixed by ligation using silk suture threads. The otherend of the catheter was fixed to the dorsal hypoderm. The incised areasof the lower back and abdomen were sutured with silk threads. Viccillin5500 (Meiji Co., Ltd., 10 mg titer/0.1 mL distilled water/rat) wasinfused into the muscle of the rump.

<Preparation of Cystometry>

The rats were anesthetized with ether and housed in a Bollmann cage 2weeks after the construction of the models. To the front end of each ofthe bladder catheters, a pressure transducer via a three-way cock wasconnected, and the intravesical pressure was recorded using a strainpressure amplifier•recorder. One end of the three-way cock was connectedto an intravesical instillation syringe mounted in an infusion pump, andthe other end was connected to an extension tube filled withphysiological saline, which was used for the discharge of residualurine. The treated rats were left until the rats came out from under theanesthesia.

<Experimental Method>

Injectable water (vehicle group) and the test compound (5 mg/kg) wereorally administered. After 1 hr, physiological saline was perfused intothe bladder at a flow rate of 2 mL/h and voiding parameters (bladdercapacity and residual urinary volume) were measured. After 1 hr ofperfusion and immediately after urination, the perfusion was stopped andresidual urine in the bladder was removed. Voiding parameters werecalculated for each cystometry. With regard to the residual urinaryvolumes, values of the vehicle group and the group wherein the testcompound was administered were compared. With regard to the bladdercapacities, values of the normal group and the test group wherein thetest compound was administered were compared.

<Results>

The results are shown in FIGS. 1 and 2. Compound 17 had no effect on thebladder capacity at a dose (0.01 mg/kg) producing a significantreduction in the residual urinary volume of the underactive bladdermodels. In contrast, comparative compound A produced a significantdecrease in bladder capacity at an effective dose (0.01 mg/kg).

It is thought that a reduction in bladder capacity than the normal levelleads to a storage symptom wherein urine cannot be stored, resulting infrequent urination, which is a side effect on the urinary system.

From the results, the compound of the present invention is effective asa therapeutic agent for underactive bladder and does not cause sideeffects on the urinary system at an effective dose.

(3) Measurement of Blood Pressures and Heart Rates in Normal Rats<Measurement Method>

The blood pressures and heart rates of female Wistar rats were measuredin accordance with the following procedure. On the day of measurement,indwelling of catheters for blood pressure•heart rate measurement wascarried out under anesthesia with ether. The back of the neck of eachrat was incised; a feeding catheter (Atom Medical Corporation) filledwith heparinized physiological saline was introduced from the back ofthe neck; the catheter was inserted into the common carotid artery; andthe surgical incision was closed. The measurements were carried out in aBollmann cage under the conscious state, and the evaluations werecarried out after confirming that the individual parameters werestabilized. After confirming the stabilization of blood pressure andheart rate, the test compound which was prepared using injectable watercontaining equimolar NaOH was orally administered at a dose of 5 mL/kg.

The catheter drawn from the back of the neck was connected to a pressuretransducer (DX-200, NIHON KOHDEN CORP.), and the blood pressures andheart rates were measured using an amplifier for pressure measurement(Gould Instrument). The blood pressures and heart rates were recordedusing a recorder (LINEARCORDERWR3320, GRAPHTEC). For each individual,rates of increase and decrease in average blood pressure and heart ratebefore administration and 30, 60, 120, and 180 min after administrationwere calculated with respect to the values of each individual beforeadministration. Changes in blood pressure and heart rate before andafter administration of the test compound were evaluated.

<Results>

FIGS. 3 and 4 shows the results obtained after administration of thecompound of the present invention (0.3 mg/kg) and the comparativecompound (0.3 mg/kg).

The compound 17 had no effect on the blood pressure at a dose ofconcentration of 0.3 mg/kg. Furthermore, the compound 17 had no effecton the blood pressure even at a dose of concentration of 1 mg/kg. Incontrast, the comparative compound A showed a tendency to increase theblood pressure at a dose of concentration of 0.3 mg/kg, and to increasean about 10% in blood pressure at a dose of concentration of 1 mg/kg.Furthermore, comparative compound B, comparative compound C andcomparative compound D showed a tendency to decrease the blood pressureat a dose of concentration of 0.3 mg/kg.

The compound 17 had no effect on the heart rate at a dose ofconcentration of 0.3 mg/kg. In contrast, the comparative compound B, thecomparative compound C and the comparative compound D produced an about20% increase in heart rate at a dose of concentration of 0.3 mg/kg.

The above results showed that the comparative compounds posses the riskof influencing the blood pressure and heart rate, whereas the compoundof the present invention has little effect on the blood pressure andheart rate.

Therefore, the compound of the present invention has little risk of sideeffects on the circulatory system.

(4) Blood Pressure and Heart Rate Measurement in Hypertensive Rats

The blood pressures and heart rates of male spontaneously hypertensiverats were measured. On the day of measurement, indwelling of cathetersfor blood pressure•heart rate measurement and subject substanceadministration was carried out under anesthesia with ether. The back ofthe neck of each rat was incised, a feeding catheter (Atom MedicalCorporation) filled with heparinized physiological saline was introducedfrom the back of the neck; the catheter was inserted into the commoncarotid artery and internal jugular vein; and the surgical incision wasclosed. The measurements were conducted in a Bollmann cage under theconscious state and evaluations were carried out after confirming thatthe individual parameters were stabilized. After confirming thestabilization of blood pressure and heart rate, the test compound wascontinuously administered intravenously at a flow rate of 5 mL/kg/h for30 min.

The catheter drawn from the back of the neck was connected to a pressuretransducer (DX-200, NIHON KOHDEN CORP.), and the blood pressures andheart rates were measured using a blood pressure amplifier (Gouldinstrument). The blood pressures and heart rates were recorded onrecording paper using a recorder (LINEARCORDER WR3320, GRAPHTEC). Theblood pressures and heart rates were converted into values on therecording paper before administration and 2.5, 5, 10, 15, 30, 45 and 60min after administration. For each individual, rates of increase anddecrease in the parameters were evaluated relative to the value beforeadministration (value at 0 min).

<Results>

The results are shown in FIGS. 5 and 6.

Compound 17 had no effect on the blood pressure. In contrast,comparative compound B reduces an about 10% blood pressure inadministration at a dose of 100 ng/kg/min. Additionally, it reduces anabout 25% blood pressure in administration at a dose of 300 ng/kg/min.

From the results, the compound of the present invention has low risk ofside effects on the circulatory system in patients suffering fromcirculatory illness such as hypertension.

(5) Digestive Symptoms

Using male rats, aged 6 weeks, general states of the rats were observedafter repeating oral administration of the test compound at a dose of0.1 mg/kg for 4 days. To a control, injectable water which is a mediumwas administered.

<Results>

No digestive symptoms such as soft feces were observed in the groupsadministered with the compound 17. In contrast, soft feces were observedin the groups administered with the comparative compound C from thefirst day after administration.

Thus, the compound of the present invention is safe without causing sideeffects on the digestive system.

(6) Evaluation of Membrane Permeability of Drugs (Oral Absorbability)

The permeability of the drugs through artificial membranes was measuredby parallel artificial membrane permeability assay (PAMPA) under thefollowing conditions. For the measurements, a PAMPA system (pION) wasused. The membrane permeability was evaluated by measuring membranepermeability coefficients at three pH values and summing the values(PAMPA(SUM)(cm/sec)).

Lipid membrane: GIT-0 (pION)

Wavelength: 190-498 nm

Incubation time: 4 hr

Incubation temperature: 25° C.

Donor: 5% DMSO-containing buffer

pH: 3 points of 5.0, 6.2 and 7.4

Compound concentration: 50 μmol/L,

<Results>

The membrane permeability coefficients of compound 17 was 59.3 cm/secwhich showed very good membrane permeability. On the other hand,membrane permeability coefficients of comparative compound E was 0.6cm/sec and it could be known that membrane permeability was low.

The results suggest that the compound of the present invention has goodmembrane permeability and is superior in oral absorbability.

(7) Evaluation of Systemic Clearance

Equimolar sodium hydroxide and injectable distilled water were added toeach of the test compounds to prepare a 1 mg/mL aqueous solution. Theaqueous solution was diluted with physiological saline until theconcentration reached 0.001 mg/mL and was rapidly administered at a doseof 0.001 mg/mL/kg to cynomolgus monkey through the cephalic vein. Viaheparinized syringes, 2 min, 5 min, 15 min, 30 min, 1 hr, 2 hr, 4 hr, 6hr, 8 hr and 24 hr after administration, blood was drawn from thecephalic vein (non-administered sites). After centrifugation, bloodplasma was sampled and stored at −80° C. before pretreatment. The bloodplasma was pretreated by mixing with acetonitrile and centrifuging toremove proteins followed by measurement by LC/MS/MS. Changes ofconcentration in blood plasma was analyzed using WinNonlin4.0.1 toevaluate the systemic clearance of the test compound.

<Results>

The systemic clearance of the compound 17 was 3.6 mL/min/kg, whichshowed slow loss from the body and continuous drug action efficacy. Incontrast, the systemic clearance of the comparative compound D was 23.9mL/min/kg, which was clearly higher clearance than that of the compound17 and very fast loss from the body in comparison with the compound 17was shown.

(8) Stability Evaluation in Lyophilized Liver Cells

KHEM5100 medium which includes human lyophilized liver cells afterdissolving (final concentration of living cells: 1×10⁶ cells/mL) and thetest compound (acetonitrile or methanol solution, final concentration≦1%) was incubated at 37° C. Immediately after reaction and with thepassage of reaction time, some portions were sampled from the medium.

The concentrations of the test compound in the samples were measured byLC/MS/MS. The residual rate of the test compound relative to immediatelyafter reaction was calculated by the following equation:

Residual rate=the concentration of the test compound in the sample afterreaction/the concentration of the test compound in the sampleimmediately after reaction×100(%)

The residual rates were plotted on a single logarithmic scale againstreaction time to calculate loss rate constants. The test was repeated(n=2), and the obtained values were averaged.

<Results>

The results are shown below.

TABLE 3 Reaction time (h) 0 0.5 1 2 Residual rate Compound 17 100 111101 82.2 Comparative compound B 100 91.5 78.1 62.3

The residual rate of comparative compound B was 80% or less 1 hr afterreaction and about 60% 2 hr after reaction. In contrast, the residualrate of compound 17 was 100% 1 hr after reaction and 80% or more even 2hr after reaction.

The results demonstrate high stability of the compound of the presentinvention against metabolism in the liver.

(9) Effects on Cardiac Function

Cynomolgus monkeys were anesthetized with pentobarbital (at an initialdose of 20-30 mg/kg by intravenous administration; at a dose of 4-5mg/kg/hr by intravenous continuous administration). A tracheal tube wasinserted and experiments were carried out under artificial respiration(fresh air+pure oxygen, ventilatory volume: 10-15 mL/kg, ventilationfrequency: 10-15 times/min). In the right lying position, the leftthorax was opened between the fourth and fifth intercostal spaces. Thecommon carotid artery (the origin of the left anterior descending arteryor circumflex branch) and the origin of the ascending main artery werepeeled off and transducers for blood flow measurement were locatedthere. The blood flow rates were measured using an electronic bloodflowmeter or an ultrasonic blood flowmeter. The blood pressures weremeasured using a pressure transducer in a state where a catheter wasinserted into the right femoral artery. The left ventricular internalpressure was measured in a state where a catheter was inserted from theleft carotid artery into the left ventricle. The electrocardiogram wasmeasured using needle electrodes installed in the right armpit and theleft thorax. After catheters for administration were inserted into theright and left cephalic veins and femoral veins, the test compound,pentobarbital (under anesthesia) or an aqueous solution (SOLITA T3containing 1.2% NaHCO₃) were administered therethrough. The testcompound was continuously administered intravenously 30 min using acontinuous infusion system. The blood pressure, left ventricularinternal pressure, blood flow rate through the coronary artery andelectrocardiogram data were simultaneously inputted to a PowerLab system(LabChart6, AD instruments) to measure/calculate average blood pressure,heart rate, average blood flow rate through the coronary artery, beatvolume, stroke volume (beat volume/heart rate), maximum first deviationof the left ventricular internal pressure, total peripheral blood vesselresistance (average blood pressure/beat volume), cardiac performance(average blood pressure×beat volume) and double product (systolicarterial pressure×heart rate), which is indicative of myocardial oxygenconsumption.

The averages of all evaluation parameters for 1 min were obtained beforeadministration, immediately after administration, and 10 min, 20 min and30 min after administration, and changes of the averages relative to thevalue measured before administration which is defined as 100% werecalculated.

<Results>

The cardiac performance and double products are shown in FIGS. 7 and 8.The compound 17 did not affect the cardiac performance and doubleproduct at doses of 30 ng/kg/min and 100 ng/kg/min. Additionally, thecompound 17 did not affect the other cardiac function parameters,including the blood flow rate through the coronary artery. In contrast,the comparative compound B had an inhibitory effect on the cardiacfunctions.

From the above, the compound of the present invention is a safe compoundwhich does not affect cardiac functions.

(10) Effects on Urinary Excretion Dysfunction Models <Construction ofAnimal Models>

Urinary excretion dysfunction models were constructed in accordance withthe following procedure. After anesthesia of cynomolgus monkeys, theregion from the suprapubic area to the abdominal area was shaved,followed by fixing in a dorsal position. The shaved region wasdisinfected and the four legs were fixed. Using an electrosurgicalknife, the skin region from the suprapubic area to the umbilical areaand the peritoneal membrane were sequentially incised, followed bydamage to the pelvic nerve and removal of the uterus. After the surgicaloperation, viccillin-containing physiological saline was added dropwiseto the incised area. The peritoneal membrane and skin of the incisedarea were sutured with silk threads and disinfected. Viccillin wasadministered for 7 consecutive days after surgery. Meloxicam wasadministered once daily for 7 consecutive days to manage pain in theperioperative period.

<Experimental Method>

The cynomolgus monkeys were seated on monkey chairs, followed byretention of the hands and legs with strings. Injectable water wasadministered orally, and physiological saline and the test compound (60ng/kg/h) were continuously administered intravenously to allow urinationfreely. The maximal urinary flow rate was measured using a urineweighing sensor.

<Results>

In the urinary excretion dysfunction model, the compound 17 showed a 61%improvement in maximal urinary flow rate over the vehicle group. Incontrast, comparative compound B and comparative compound D showed only27% and 36% improvement in maximal urinary flow rate over the vehiclegroup.

From the results, it was shown that the compound of the presentinvention is very effective in promoting urination.

The results obtained in Biological Examples (1) to (10) reveal that thecompound of the present invention has a bladder contracting activity anda urethral relaxing activity and high promoting urination activity.Additionally, the compound of the present invention is a compound whichis superior in safety and can avoid all risk of side effects on theurinary system, circulatory system and digestive system, which could notbe achieved by any compounds described in prior art. Furthermore, thecompound of the present invention has excellent pharmacokineticsincluding oral absorbability and metabolic stability.

Formulation Examples Formulation Example 1

The compound 17 (5.0 g), calcium carboxymethyl cellulose (20 g),magnesium stearate (10 g) and microcrystalline cellulose (920 g) weremixed by a general method, followed by compression to produce 10,000tablets wherein 0.5 mg of the active ingredient was present in each ofthe tablets.

Formulation Example 2

The compound 17 (2.0 g), mannitol (500 g) and distilled water (10 L)were mixed by a general method, followed by sterilization by a generalmethod. 1 mL of the solution was filled in a vial and frozen-dried by ageneral method. A total of 10,000 vials were obtained wherein 0.2 mg ofthe active ingredient was present in each of vials.

INDUSTRIAL APPLICABILITY

The compound of the present invention has a contracting activity ofbladder detrusor and a relaxing activity of urethral sphincter.Therefore, the compound of the present invention can ameliorate bladdercontraction dysfunction and/or urethral relaxation dysfunction and isparticularly effective as an agent for preventing and/or treatingunderactive bladder. Additionally, the compound of the present inventionis effective as an agent for ameliorating various symptoms associatedwith underactive bladder. Furthermore, the compound of the presentinvention is very safe and exhibits excellent pharmacokinetics,including oral absorbability etc. Therefore, the compound of the presentinvention is very useful as a medicament.

1. A compound represented by formula (I):

wherein

represents an α-configuration;

represents a β-configuration; and

represents an α-configuration, a β-configuration or an arbitrary mixturethereof, a salt thereof, a solvate thereof, a prodrug thereof, or amixture with a diastereomer thereof in an arbitrary ratio, or acyclodextrin clathrate thereof.
 2. The compound of claim 1, wherein thecompound is (1)2-[(2-{(1R,5R)-2-oxo-5-[(1E)-7,8,8-trifluoro-4-hydroxy-4-methyl-1,7-octadien-1-yl]cyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid, (2)2-[(2-{(1R,5R)-2-oxo-5-[(1E,4S)-7,8,8-trifluoro-4-hydroxy-4-methyl-1,7-octadien-1-yl]cyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid, or (3)2-[(2-{(1R,5R)-2-oxo-5-[(1E,4R)-7,8,8-trifluoro-4-hydroxy-4-methyl-1,7-octadien-1-yl]cyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid.
 3. The mixture in an arbitrary ratio of claim 1, wherein thecompound is2-[(2-{(1R,5R)-2-oxo-5-[(1E,4S)-7,8,8-trifluoro-4-hydroxy-4-methyl-1,7-octadien-1-yl]cyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid and the diastereomer is2-[(2-{(1S,5R)-2-oxo-5-[(1E,4S)-7,8,8-trifluoro-4-hydroxy-4-methyl-1,7-octadien-1-yl]cyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid.
 4. A pharmaceutical composition comprising, as an activeingredient, a compound represented by formula (I):

wherein all of the symbols have the same meanings as defined in claim 1,a salt thereof, a solvate thereof, a prodrug thereof, or a mixture witha diastereomer thereof in an arbitrary ratio, or a cyclodextrinclathrate thereof.
 5. The pharmaceutical composition of claim 4, whereinthe pharmaceutical composition is an agent for contracting the bladderdetrusor and relaxing the urethral sphincter.
 6. The pharmaceuticalcomposition of claim 5, wherein the pharmaceutical composition is anagent for preventing, treating and/or ameliorating bladder contractiondysfunction and/or urethral relaxation dysfunction.
 7. Thepharmaceutical composition of claim 6, wherein the bladder contractiondysfunction and/or the urethral relaxation dysfunction is underactivebladder.
 8. A medicament comprising a compound represented by formula(I):

wherein all of the symbols have the same meanings as defined in claim 1,a salt thereof, a solvate thereof, a prodrug thereof, a mixture with adiastereomer thereof in an arbitrary ratio, or a cyclodextrin clathratethereof, and at least one drug selected from α1 receptor antagonists andacetylcholinesterase inhibitors in combination.